The central goal of this proposal is to define how proteoglycans modulate the lung innate immune response in pneumococcal pneumonia. Streptococcus pneumoniae, the pneumococcus, is the most common causative agent of community-acquired bacterial pneumonia. It is estimated that this Gram-positive bacterium causes 500,000 cases of pneumonia and 40,000 deaths annually in the US. Syndecan-1 is a major cell surface heparan sulfate proteoglycan of epithelial cells that can function as a soluble proteoglycan in the extracellular environment because its ectodomain is shed by metalloproteinases under inflammatory conditions. S. pneumoniae induces syndecan-1 shedding by activating host cells through a secreted factor and directly cleaving syndecan-1 ectodomains through ZmpC, a metalloproteinase virulence factor for its lung infection. Preliminary data suggest that S. pneumoniae-induced syndecan-1 shedding is a key virulence mechanism in the pathogenesis of pneumococcal pneumonia. The underlying mechanisms of how syndecan-1 shedding promotes pneumococcal pneumonia are not known, but shedding enhances CXC chemokine-induced neutrophil infiltration in mice, and shed ectodomains inhibit several antibacterial factors expressed in airway surface fluids in a heparan sulfate (HS)-dependent manner. Further, syndecan-1 null mice show attenuated pneumococcal pneumonia relative to wild type mice. Based on these data, this proposal will test the hypothesis that S. pneumoniae subverts syndecan-1 shedding to dysregulate the lung innate immune response and promote its pathogenesis in 3 Specific Aims. Aim 1 will determine the molecular and cellular details of how S. pneumoniae induces syndecan-1 shedding. Aim 2 will define the structural features of syndecan-1 that promote pneumococcal pneumonia and determine if HS is a therapeutic target for anti-pneumococcal pneumonia therapy. Aim 3 will identify the biological targets of syndecan-1 ectodomains in pneumococcal pneumonia. It is anticipated that these studies will define the key mechanisms of syndecan-1 in pneumococcal pneumonia, and provide a foundation for the design and development of novel therapeutic approaches to combat pneumococcal lung diseases. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae is a major human pathogen that is the primary cause of bacterial pneumonia. However, how this bacterium causes lung disease is incompletely understood. The goal of this proposal is to define how S. pneumoniae takes advantage of our own molecules to promote its infection, using state-of-the- art molecular, biochemical, cell biological, and gene targeting approaches. Successful completion of the proposed studies is anticipated to define the underlying mechanisms and identify new means of brining pneumococcal lung diseases under better control.